Primary glomerular diseases like focal and segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are a major cause of morbidity in the kidney disease population. FSGS patients often progresses to end stage kidney failure. The long term goal of the PI's lab is to develop novel mechanism - based therapeutic agents that will reduce the progression of chronic kidney disease due to glomerular disorders. Reducing the progression of chronic kidney disease to end stage kidney disease will have a major positive social and financial impact in the United States and worldwide. The PI's laboratory first published the expression of a relatively new family of transcriptional factors, th zinc Fingers and Homeoboxes (ZHX) proteins, in podocytes nearly eight years ago. After working diligently on all three family members for a decade, PI and co-investigator have made several interesting observations about the second member of this family, ZHX2, in the context of glomerular diseases. It appears that ZHX2 interacts with at least two proteins present on the podocyte cell membrane. Aminopeptidase A (APA) is present over the entire podocyte surface, whereas Ephrin B1 is present in the slit diaphragm. Studies conducted by our group suggest that the ZHX2-APA relationship may form a basis for upstream pathways in the pathogenesis of MCD, whereas the ZHX2-Ephrin B1 interaction could potentially very significantly influence the development of FSGS. In Specific Aim 1, the team will investigate the importance of the ZHX2-APA interaction in the pathogenesis of MCD related molecular changes using a combination of mutant mice and animal models of human disease. In Specific Aim 2, we will test to see how the ZHX2-ephrin B1 interaction participates in the development of FSGS. Several mutant mice and animal models will be used. We will also test if this protein interaction can be linked with other proteins expressed in podocytes that have gene mutations in patients with FSGS. In Specific Aim 3, a new rat model of low level ZHX2 overexpression in podocytes will be used to establish proof of principle for future therapeutic interventions that utilize increasing podocyte ZHX2 expression to treat human glomerular diseases.